A synthetic peptide, T2O, representing a discrete region of the HlV fusion protein, gp4l, effectively blocks virus-mediated cell to cell fusion as well as de novo virus infection of T-cells. While T20 is promising as a peptide therapeutic, it could exhibit a limited delivery profile characteristic of peptide therapeutics. T20 binds selectively to soluble forms of HIV-1 gp4l from which it was derived. Using the screening assays developed in Phase I, we have identified more active peptides from which a T20 backup peptide will be chosen. In order to ultimately identify compounds having oral availability, we will use these screening assays to find a small molecule mimic of T2O inhibition of HIV-1 fusion and infection. The long term objectives of this proposal are to discover and develop a novel class of antivirals for the treatment of HIV infection and AIDS. We propose to develop a high through-put biochemical screen based on the binding of T20 to gp4l analogs as a first step in identifying new antiviral leads. Our specific aims are: (1) To select a second generation lead antiviral peptide with improved activity against HIV. (2) To screen a minimum of 100,000 additional compounds derived from highly diverse synthetic chemical libraries with automated antibody-based and direct binding assays. (3) To establish a partnership with at least one commercial entity possessing large diverse chemical and/or natural products libraries. (4) To determine antifusion activity of small molecule screening assay "hits" in viral and cell-based fusion assays. (5) To implement preclinical development plan after selection of lead peptide or small molecule compound(s). PROPOSED COMMERCIAL APPLICATION: The objectives set forth in this proposal are designed to identify a novel class of viral therapeutics targeted to HIV fusion which will have utility in the treatment of HlV infection in AIDS. Currently approved therapies for HIV infection target the viral RT and protease. Inhibitors of viral fusion would be mechanistically distinct from approved HlV antivirals and could find utility as both stand alone therapy and combination therapy with existing drugs.